Medicament carrier

ABSTRACT

A controlled release insert for a living eye consisting of a biologically effective form of pilocarpine and a biologically inert biodegradable carrier consisting essentially of poly(Nacetyl-6-O-(carboxymethyl)-D-glucosamine) gives effective treatment to the human eye for prolonged periods. Other medicaments and other enzymatically degradable forms of poly(Nacetyl-D-glucosamine) may be used for rate controlled release in the eye and other areas.

United States Patent Capozza Oct. 7, 1975 1 MEDICAMENT CARRIER OTHER PUBLICATIONS [75] Inventor: R'chard Carl Capella Norwalk' Worden Rayon Textile Monthyl, Sept. 1941, XXIKQ),

Conn p 49 Developments in Organic NonCellulosic Fi- {731 Assignee: American Cyanamid Company, bmus Materials-v Stamford, Conn Chem. Abstracts 79 No. 32258n, (1973). [22] Filed: Febll 974 Chem. Abstracts 73 No. 43828011970),

l l pp NO-i 441,6 5 Primary ExaminerShep K. Rose Attorney, Agent, or FirmSamuel Branch Walker [52] US. Cl. 424/22; 128/260; 424/19 1511 1111. C1. A61K 9/52 1 1 ABSTRACT [53] Field of Search 128/260 3355; A controlled release insert for a living eye consisting 424/l922 of a biologically effective form of pilocarpine and a biologically inert biodegradable carrier consisting es 1 Retflences Clled sentially of polylN-acetyl-6-O-(carboxymethyl)-D- UNITED STATES PATENTS glucosamine] gives effective treatment to the human 2.040379 5/1936 Rigby 260/54 eye for prolonged periods. Other medicaments and 2940,8811 5/1936 Rigby 18/54 other enzymatically degradable forms of poly(N-acet- 2,168,374 8/1939 Thor 1 1 1 260/210 yl-D-glucosamine) may be used for rate controlled re 3,632.754 1/1972 Balassa 1 1 1 1. 424/180 lease in the eye and other areas, 3,736.646 6/1973 Schmitt et al l28/335.5 X 1845.201 10 1974 Huddad et a1, 1. 424/19 6 Clam, N0 Drawmgs MEDICAMENT CARRIER BACKGROUND OF THE INVENTION This invention relates to the controlled release of drugs. The time of release of medicaments or drugs can be in part controlled by incorporating the drugs in a matrix of an enzymatically degradable form of poly(N-acetyl-D-glucosamine) so that said form is slowly enzymatically degraded over a period of time by body fluids and the drug is released into the body fluids at the time of use for a longer period than the drug would be released without the matrix carrier.

The prior art shows many efforts over a long period by many individuals to alter the rate of release of drugs. Where it is considered that drugs may be administered to many areas and for many different conditions and that various drugs have different solubilities in both water and oil, and the period for desired administration may vary from almost instantly to a long period of up to and including years, it can be seen that there is a wide range of medicaments and a wide range of conditions to be controlled.

DESCRIPTION OF THE PRIOR ART US. Pat. No. 2,552,027, Bird and Rochow, May 8, 195], CASTING Gelatine TABLETS, discloses the incorporation of medicaments, particularly vitamins, into a gelatin-glycerine matrix, which are particularly useful for the administration of vitamins or other pharmaceutical materials which should be released in the stomach or digestive tract at comparatively slow rates."

In US. Pat. No. 3,604,417, Stolzenberg and Linkenheimer, Sept. 14, 197] OSMOTIC FLUID RESER- VOIR FOR OSMOTICALLY ACTIVATED LONG- TERM CONTINUOUS INJECTOR DEVICE osmotic pressure is used to propel a piston system so that a drug is slowly injected.

Many coating systems have been used on tablets for enteric release in which various capsules have been coated either as a single tablet or by coating particles in the tablets or capsules so that drugs are released into the stomach or intestine at a controlled rate and for a longer period than would result from the administration of the medicament without such coatings.

US. Pat. No. 3,739,773, Schmitt and Polistina, June 19, 1973, POLYGLYCOLIC ACID PROSTHETIC DEVICES, in Column 6, line 53, refers to polyglycolic acid in combination with other products as slowly digestible drug release devices. This patent in Column 7, lines 47 and following, mentions that dyes, antibiotics, antiseptics, anesthetics, and other materials may be present in polyglycolic acid devices. This last language also appears in Column 3, line 48 and following of US. Pat. No. 3,297,033, Schmitt and Polistina, Jan. l0, I967, SURGICAL SUTURES.

US. Pat. No. 3,435,008, Schmitt, Epstein and Polistina, Mar. 25, I969, METHOD FOR PREPARATION OF ISOMERICALLY PURE B-GLYCOLIDE AND POLYMERIZATION METHOD FOR GLYCOLIDE COMPOSITIONS EMPLOYING PARTIAL HYDRO- LYZATE OF SAID B-GLYCOLIDE in Column 7, line 19 and following, discloses glycolide polymers as coatings for medicaments to alter their digestive characteristics.

U.S. Ser. No. l79,l29, filed Sept. 9, I971, by Takeru Higuchi, Anwar A. Hussain and John W. Shell, and the Netherlands rights to which are assigned to the Alza Corporation, is referred to in the Derwent Publications, LTD. Patent Index, and is available through conventional documents in the file of Netherlands 7,2 l2,272, in Example l4 discloses a bioerodible ocular insert containing pilocarpine free base using a matrix of polyglycolic acid. Pilocarpine is mixed with polyvinyl alcohol and used as a core between two sheets of polyglycolic acid. (see page I 12). Page discloses polyesters of lactic and glycolic acid as a carrier. Page 73, line ll, mentions chitin among other polysaccharides and plant hydrocolloids. Presumably, the reference is to the naturally occurring form of chitin. Claim 5 is drawn to bioerodibility by enzymatic cleavage. Claim 14 is drawn to cross-linked gelatin. Claim 50 is drawn to polylactic 0r polyglycolic release rate controlling materials.

Sterile peanut oil and similar materials have been used as a repository for penicillin for some time. The penicillin is slowly released from the repository. Unfortunately, the peanut oil or beeswax remains behind and is apt to form a sterile abscess rather than be absorbed by tissues.

Carboxymethylchitin is disclosed in Carbohyd. Res. 7, 483-485 (1968), Ralph Trujillo.

This article mentions the hydrolysis of both chitin and carboxymethylchitin by lysozyme.

Chitin has been estimated to be the second most abundant polysaccharide in nature with a synthesis in the neighborhood of a billion tons a year by marine organisms. See Chitin, N. V. Tracey, Reviews of Pure and Applied Chemistry, Royal Australian Chemical Institute, Vol. 7, No. l, March I957, pages I to l4.

The above patents and articles are herein hereby incorporated by this reference thereto for background information on chitin, its properties and derivatives.

Although it is well recognized that systems for the controlled release of drugs are very much in demand, the wide range of requirements is such that useful contributions are still being sought and major efforts are being made by many research organizations to improve drug delivery devices.

SUMMARY OF THE INVENTION It has now been found that enzymatically degradable forms of poly( N-acetyl-D-glucosamine) sometimes herein abbreviated as PAG, are comparatively storage stable and resistant to hydrolytic degradation so that medicaments may be incorporated and stored in a matrix of such biodegradable form of PAG, and the medicament then released in the tissue of living mammals by the enzymatic degradation of the biodegradable form of PAG. The enzyme lysozyme is particularly effective in the enzymatic degradation of the biodegradable forms of PAG. Various forms of PAG may have different degradation rates, and the degradation rate may vary with the location of the drug release device.

Usually it is desired that the drug release device be mechanically acceptable at a location of use. For instance, an ocular insert may be designed to be placed adjacent to the eyeball inside the eyelid, in the cul-desac of the conjunctiva between the schlera of the eyeball and the lid. An insert needs to be soft so that it will cause a minimum of irritation to the eyeball and the degradation products are preferably such that they may be washed away by the flow of tears without the necessity for removal of the device after its drug content has been delivered. For other locations, such as implanta- 3 4 tion beneath the surface of the skin or insertion in the Poly( N-acetyl-D-glucosamine) is a major component uterus as an anti-fertility device, the likelihood ofirrita of naturally occurring chitin. The naturally occurring tion from the mechanical aspects of the device are mat i l has not only the poly(N-acetyl-D much less. glucosamine) but also inorganic salts thought to be Because the requirements for use in the eye are 5 forms of calcium carbonate and proteinaceous mateamOrtg h m e Tig I' h p e nt device Will be rial, the composition of which is not presently known. scribed Particularly in Conjunction Wllh use in y The term chitin" is used herein to refer to the various although ll l5 be lmdel'smod that the device in naturally occurring forms of chitin including the promany form ay b0 used n Other lOCflllOHS tein and inorganic carbonate components. The term N-acetyl-D-glucosamine ha he form purified chitin" is used to refer to chitin after purifica- 6 tion to remove calcium carbonate and other inorganic H OH salts and various proteins which may be present and is K essentially poly(N-acetyl-D-glucosamine). Some con- 5 fusion exists in the literature in that the name chitin is H used as a name for poly( N-acctyl-D-glucosamine) with- H 1 out specifying whether it is a naturally occurring material containing inorganic salts and proteins or whether H 3 E the term is intended to designate purified poly(N-acetu 5 yl-D'glucosamine) without specifying the degree of pu- O rity or the character of the impurities present. or The term enzymatically degradable form of poly( N- acctyl-D-glucosamine)" refers both to the purified poly( N-acetyl-D-glucosamine) from chitin itself as well as the carboxymethyl, hydroxyethyl, and O-ethyl derivatives, etc.

The carboxymethyl derivative, properly called poly[- N-acetyl-6-O-( carboxymethyl )-D-glucosamine] has the formula a, 0011 COOH NHAc NHAc v cH 00H coon The hydroxyethyl derivative, properly called poly[N- Groups below the plane of the paper are shown by a y y y y g has thc dotted bondv formula H OCH CH OH HQ NHAC l I W o I 0 We cm ocH 0H, OH

P0ly(N-acetyl-D-glucosamine) has ascribed to it the The O-ethyl derivative. properly called poly-[N- formula (ring hydrogens omitted for clarity) acetyl-G-O-(ethyl)-D-glucosamine] has the formula 6 (3H. OH

\O/ z I l 0 s HO- NHA on ocii on,

III

The above forms are sometimes hereinafter designated by the Roman Numeral below the formula,

Other similar derivatives which are enzymatically degradable, particularly by lysozyme, are included within the generic term enzymatically degradable form of poly(N-acetyl-D-glucosamine)."

Because of the nature of the polymers, carboxymethylation, hydroxyethylation, or ethylation may not be l71 and may in part occur on the 3-hydroxyl. Unless otherwise specified, under or over-substitution of the poly[ N-acetyl-6-0-( carboxymethyl )-D-glucosamine] is to be included as a biodegradable form of PAS. The solubility in a specified solvent is one test of the degree of substitution. For example, the ()-ethyl derivative is water soluble when the ethyl group to glucosamine ratio is about i and organic soluble when the degree of substitution is greater than 1.

The term drug" is used to refer to a substance other than a food intended to affect the structure or function of the body of man or other animal. The term is some what broader than medicine in that the term medicine" is sometimes considered to be restricted to an agent which is administered to affect or control a pathogenic condition. The broader term drug here is also used to include steroids and other fertility controlling agents which may be incorporated in an intrauterine contraceptive device or other materials which may be included to affect the fertility of females or males either as an intrauterine device or subcutaneously.

The term dispensing" is used to designate a method of administering a drug to man or other animal and includes the release of the drug to a desired location. This would include the eye, gastrointestinal tract (alimentary), intrauterinely, intramuscularly, subcutaneously, or into the mucosa of the nose, mouth (sublingual), or rectum, etc. The release over a prolonged period of time designates any decrease in the release rate of the drug over that which would be expected if the drug were administered alone and would include from the matter of a few minutes as, for example, in an ocular insert containing pilocarpine to a duration of six months to a year which might be desired for the administration of a steroid in an intrauterine contraceptive device. For some conditions, even a longer period of administration, such as the lifetime of the patient, could be desired but usually a period of a very few hours up to about six months includes the medically preferred range.

Because the enzymatically degradable form of poly-(N-acetyl-D-glucosamine) is a solid which can be removed, a longacting repository pellet for insertion beneath the skin is quite practical as if for any medical reason it is desired to discontinue administration of the drug, the insert with the remaining drug charge may be removed simply by excision.

The term enzymatically degradable" refers to a form of poly( N-acetyl-D-glucosamine) or its derivatives which is broken down into body fluid soluble components and which are washed out as in tears, or transported elsewhere by tears, or other body fluid, and later degraded further or metabolized by the body or excreted by the body. The problem of retention by the body or disposal of the residual matrix is minimal or non-existent.

While other enzymes may also affect the enzymatic degradation of the poly( N-acetyl-D-glucosamine) matrix, the enzyme which is most widely distributed in the body and here very effective is lysozyme. Lysozyme occurs in practically all of the body fluids, particularly the tears, and effectively breaks down the polymer chain to water soluble or disposable components.

Chitosan, which is a common name for the deacylated form of poly(N-acetyl-D-glucosamine), and which is poly(D-glucosamine) is not enzymatically degradable by lysozyme.

By contrast, the present enzymatically degradable forms of poly( N-acetyl-D-glucosamine) are not readily hydrolyzed by water. For instance, I in a phosphate buffer at pH 7.2 at 37C for 24 hours is not hydrolyzed whereas under the same time and temperature in the presence of lysozyme hydrolysis occurs,

It is highly advantageous to have the degradation of the enzymatically degradable form of poly(N-acetyl-D- glucosamine) occur only by the action of an enzyme as the resistance to hydrolytic degradation markedly reduces problems of manufacture and storage in the presence of ambient moisture, and ensures a steady smooth surface erosion rather than a fragmentation process commonly experienced by polymers which are hydrolyzed by small molecules.

Any of the drugs used to treat the eye and surrounding tissues can be incorporated with the enzymatically degradable form of PAG of this invention. Also, it is practical to use the eye and surrounding tissues as a point of entry for systemic drugs that enter circulation in the blood stream and produce a pharmacological response at a site remote from the point of application of drug and the enzymatically degradable form of PAG matrix. Thus, drugs which will pass through the eye or the tissue surrounding the eye to the bloodstream, but which are not used in therapy of the eye itself, can be incorporated in the enzymatically degradable PAG matrix.

Suitable drugs for use in therapy of the eye with the present insert include, without limitation: Antiinfectives: such as antibiotics, including tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin; sulfonamides, including sulfacetamide, sulfamethazole, and sulfisoxazole; antivirals, including idoxuridine; and other anti-infectives including nitrofurazone and sodium propionate; Antiallergenics such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine; Anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, triamcinolone, medrysone, prednisolone, prednisolone 2l-phosphate and prednisolone acetate. Decongestants such as phenylephrine, naphazoline, and tetrahydrazoline', Miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, disopropyl fluorophosphate, phospholine iodide, and demecarium bromide; matropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine and sympathominetics such as epinephrine. Drugs can be in various forms, such as unchanged molecules, components of molecular complexes, or nonir ritating, pharmacologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. Furthermore. simple derivatives of the drugs (such as ethers, esters.

amides. etc.) which have desirable retention and re lease characterics but which are easily hydrolyzed by body pH, enzymes. etc. can be employed. The amount of drug incorporated in the ocular insert varies widely, depending on the particular drug, the desired therapeutic effect, and the time span for which the ocular insert will be used. Since the ocular insert is intended to provide the complete dosage regime for eye therapy for but a particular time span, such as 24 hours, there is no critical upper limit on the amount of drug incorporated in the device. The lower limit will depend on the activity of the drug and its capability of being released from the device. Thus, it is not practical to define a range for the therapeutically effective amount of drug incorporated into the device. However, typically, from I mi crogram to l milligram of drug is incorporated in each insert.

In each case, the polymeric material used to form the ocular insert is chosen for its compatibility with a particular drug and its capability of releasing that drug at an appropriate rate over a prolonged period of time. Specific, but nonlimiting, examples of combinations of drugs and polymers for use in forming the ocular insert include: poly- N-acetyl-6-O-(carboxymethyl )-D- glucosamine] and epinephrine; poly[N-acetyl-6-0- (carboxymethyl)-D-glucosamine] and mixture of pilocarpine hydrochloride and epiniphrine; poly[Nacetyl- 64H 2 '-hydroxyethyl )-D-glucosamine] and acetazolamide; poly[N-acetyl-b-(J-(ethyl)'D-glucosamine] and phospholine iodide; poly[N-acetyl-fi-(carboxymethyl)-D-glucosamine] and triamcinolone, or in general any of the drugs listed above and the enzymatically degradable form of poly(N-acetyl-D-glucosamine), including degrees of substitution greater or less than l, and related derivatives such as other lower alkyl derivatives instead of poly[ N-acetyl-o-0-( ethyl )-D- glyucosamine], other carboxyalkyl derivatives, and their esters and salts, hydroxyalkyl derivatives, etc.

The degradation rate of the enzymatically degradable form of poly(N-acetyl-D-glucosamine) can be lowered by cross-linking, if a slower release rate is preferred.

The ocular insert can be fabricated in any convenient shape for comfortable retention in the cul-de-sac. It is important. however, that the device have no sharp, jagged. or rough edges which can irritate the sensitive tissues of the eye. Thus, the marginal outline of the ocular insert can be ellipsoidal, bean-shaped, rectangular, etc. in cross section, it can be concavo-convex, rectangular, etc. As the ocular insert is flexible and, in use, will assume essentially the configuration of the seleral curvature, the original shape of the device is not of controlling importance. Dimensions of the device can vary widely. The lower limit on the size of the device is governed by the amount of the particular drug to be applied to the eye and surrounding tissues to elicit the de sired pharmacological response, as well as by the smallest sized device which conveniently can be inserted and removed from the eye. The upper limit on the size of the device is governed by the limited space within the cul de-sac that conveniently and comfortably can be filled with an ocular insert. Typically, the ocular insert is 4 to millimeters in length, l to 12 millimeters in width, and 0.l to l millimeter in thickness. Preferably, it is ellipsoidal in shape and about 6 X 4 X 0.5 millimeters in size.

While particularly convenient for an insert in the eye, the matrix containing the drug of the present invention can include other drugs for other areas. For instance, if the drug is to be taken orally, a tablet of a size and shape adapted to being swallowed is preferred. If it is to be placed subcutaneously, a tablet or rod such that it may be placed under the skin in an appropriate location is selected. The amount of drug and the time over which it is to be dispensed are controlling in the choice of size of the implant.

While the drug may be combined with the enzymatically degradable form of PAG matrix in any convenient way, it is particularly convenient to dissolve both in a common solvent which permits casting of the enzymatically degradable form of PAG as a matrix containing the drug to be dispersed therein.

Poly(N-acetyl-Dglucosamine) is reported to be in soluble in all solvents except 88% phosphoric acid which badly degrades the polymer. Unexpectedly, it has now been found that hexafluoroisopropanol (HIPA) and hexafluoroacetone sesquihydrate (HFAS) are solvents for the polymer, These are extremely powerful solvents, and so much so that care must be used in selecting drugs which are compatible with such solvents to form solutions for casting.

I Poly[ N-acetyl-6-()-( carboxymethyl )-D- glucosamine], l, poly[N-acetyl-(J-O-(2'-hydroxyethyl) D-glucosamine], ll, and poly[N-acetyl-6-O (ethyl J-D- glucosamine], III, are preferred because of cosolubility with many drugs in common solvents, including water. Non-toxic solvents are preferred.

l and II are water soluble at the 5% level, and III is water soluble at the 5% level if the degree of substitution is not more than about 1, and organic solvent soluble if more than about 1. Organic solvents may be used such as alcohols, chloroform, benzene, toluene, mix tures of benzene and toluene with alcohols and l e tones.

Pilocarpine or other drugs can be incorporated into matrices of these enzymatically degradable forms of PAG by hydrogen bonding, covalent bonding, ionic bonding or simple entrapment. The matrices themselves can be variably crosslinked with a variety of physical and chemical agents. They can be sterilized and when hydrated become quite pliable, while retaining adequate strength to resist manipulation.

Present day therapy of topical drug application consists of drops and ointments. There are several deficiencies associated with these methods of delivery 1 it is impossible to achieve 24 hour control of the disease (2) it is wasteful with respect to the amount of drug used (3) some people show strong sensitivity to cholinergic and adrenergic drops (4) many patients fail to apply the medication as directed resulting in poor control of the disease (5) side effects result from the drug passing through the lachrymal duct into the circulatory system. The herein described invention eleminates these problems and provides a means of releasing medication into the tear films in therapeutic levels continuously. The device is biodegradable and, hence, it is not necessary to remove from the eye and also capable of delivering large dosages giving it broad drug applicability. This invention constitutes a more efficient means of drug delivery that prolongs and enhances the drug effect.

As the scope of this invention is broad, it is illustrated by the following typical examples in which temperatures are centigrade, and parts are by weight unless clearly otherwise specified.

EXAMPLE 1 Purification of Chitin A commercial grade of chitin (Cal-Biochemicals) was finely ground in a ball mill overnight to pass a 6 mm screen and be retained by a 1 mm screen. 149 g. of this finely ground material was decalcified by extracting with 825 ml. of 2N HCl at 4C for 48 hours, in a flask stirred with a magnetic stirrer. The material was collected by centrifugation and washed repeatedly with water until neutral. The ash content was 04-05%. The decalcified chitin was then stirred at room temperature with 1500 m1. of 90% formic acid overnight. The mixture was centrifuged and the residue repeatedly washed with water. The washed chitin was then suspended in 2 l. of NaOH solution and heated at 90l00C. for 2.5 hours. The solution was filtered, the cake washed with water until neutral, washed several times with absolute ethanol and ether, and dried at 40 C. under reduced pressure; yield 66 g. of poly( N-acetyl-D- glucosamine). Infrared spectrum (KBr pellet) shows bands at 3500 cm" (S), 2900 (W), 1652 (S), 1619 (S), 1550 (S), 1370 (S), 1300 (M), 1070 (Broad). (S is strong, M is medium, W is weak).

EXAMPLE 11 Poly N-acetyl-6-0-( carboxymethyl )-D-glucosamine] 15 g. of the poly(N-acetyl-D-glucosamine) from Example l was swollen with 100 ml. of dimethylsulfoxide (DMSO). To this highly swollen suspension was added 400 ml. of 2-propanol and the mixture was stirred vigorously under nitrogen while 40 ml. of aqueous NaOH was added over an interval of 30 minutes at room temperature. After stirring for an additional hour, 18 g. of chloracetic acid dissolved in 40 ml. of water was added dropwise over a 30 minute period. The mixture was then heated at 55C. for 24 hours. The mixture was decanted and to the residue was added 100 ml. of 70% methanol. The suspension was then neutralized with 5 ml. of 90% acetic acid. The mixture was filtered, washed with 70% methanol, absolute methanol and dried at 40C. in vacuo. Yield 24 g. of poly[N- acetyl-6-0-(carboxymethyl)-D-glucosamine], l. lnfrared (KBr pellet) shows bands at 3500 cm. (S), 2900 (M), 1600 Broad (S), 1400 (M), 1320 (M), 1100 Broad (S). A sample was titrated and shown to have 4.03 meq acid/g indicating 100% of the repeating mers were carboxylated. Films easily removed from glass were cast from water solution and shown to be transparent, flexible and tough.

EXAMPLE [[1 Preparation of poly(D-glucosamine) A procedure similar to that described by P. Broussignoc, Chemie and lndustrie, 99 (9) (68), 1243 was used. To a solution of 180 g. of 96% ethanol and 180 g. ethylene glycol was added 360 g. KOH with stirring. To this solution was then added 54 g. of poly(N-acetyl-D- glucosamine) (purified Chitin) from Example I and the mixture heated at 120C. for 6 hours. After cooling an equal volume of water was added to the mixture. The mixture was filtered and washed several times with water until neutral, then twice with acetone, and dried in vacuo. Yield 42.6 g. of poly(D-glucosamine), sometimes called chitosan. Infrared spectrum (KBr pellet) showed bands at 3450 cm. (S), 2900 (M), 1620 (S), 1600 (S), 1370 [Broad (5)], 1050 [Broad (5)]. Upon potentiometric titration of the sample 81.4% of the mers were found to be deacylated. The product is soluble in 3% acetic acid and forms clear, flexible, tough films from this solution. lt is not enzymatically biodegradable by lysozyme.

EXAMPLE IV Poly(D-Glucosamine )lPilocarpine Film To 5 ml. of 3% acetic acid was added 0.25 g. of poly(D-glucosamine) from Example 111. To the solution thus formed was then added 50 mg. pilocarpine free base and 100 ul of tritiated pilocarpine, and the mixture was cast as a film (40 mil wet thickness) on glass. This film was crosslinked by dipping the film in 37% formaldehyde solution for 5 hours. This film showed zero order release over a period of 3 days at which time it was still releasing pilocarpine at a zero order rate. About percent of the pilocarpine remained in the film matrix after 3 days. The use of tritiated pilocarpine permits the use ofa liquid scintillation counter to monitor the release rate accurately and conveniently. Radiological hazards are associated with such tritiated material in the treatment of human subjects so experimental animals are preferred to study release rates.

EXAMPLE V Poly[N-Acetyl-6-0-( carboxymethyl )-D- Glucosamine]/Pilocarpine Film To a 5% solution of poly[N-acetyl-6-0-carboxymethyl)-D-glucosamine] (0.95 g.) in water was added 50 mg. of pilocarpine nitrate and 100 ul of tritiated pilocarpine. A film 40 mils thick was cast on a glass plate and allowed to dry. The film was crosslinked by dipping into 10% alum for 5 hours. Release of pilocarpine from this film in an aqueous solution approximating human tears is essentially first order, with of the pilocarpine being released within about 5 hours.

EXAMPLE V1 Poly( N-Acetyl-D-Glucosamine) Matrix Membranes of poly(N-acetyl-D-glucosamine) were prepared by dissolving poly(N-acetyl-D-glucosamine) in each of hexafluoroacetone sesquihydrate (1.4% solution) and hexafluoroisopropanol (2% solution). The films were tough, transparent, non-tacky, flexible and were quite pliable when hydrated yet retained adequate strength to resist manipulation. The membranes showed no hydrolysis after exposure to water for 5 days. In the presence of lysozyme, however, the films were degraded slowly. The films eroded release any drug in the film slowly.

EXAMPLE Vll Biodegradability of Poly[ N-Acetyl-6-0-(carboxymethyl )-D-Glucosamine] After 24 hours incubation at 37C. in phosphate buHer pH 7.2 containing 1500 units/ml of lysozyme, poly[ N-acetyl-6-0-( carboxymethyl )-D-glucosamine] was hydrolyzed to oligomers as determined by Gel Permeation Chromatography. A control containing no enzyme was not hydrolyzed under the same conditions.

EXAMPLE Vlll In Vivo Results Using Polyl N-Acetyl-6-O-( Carboxymcthyl )-D- Glucosamine]lPilocarpine Membranes of poly[ N-acetyl-6-0-( carboxymcthyl Dglucosamine] were evaluated in vivo for sustained pharmacological effect and eye irritation. ln the right eye of each of three rabbits was placed a l mm X l l EXAMPLE lX Poly[ N-Acetyl-60-( 2 '-Hydroxyethyl )-D- Glucosamine] Into a screw cap bottle was placed 13.6 g. of purified PAG milled so that it passes a 1 mm. sieve. To the bottle was added 200 ml. of cold (05C.) aqueous 43% NaOH and the contents stirred for 2 hours under nitrogen and then held at 04C. for [0 hours. The swollen alkali derivative was then squeezed to 3 times its original weight in a sintered glass funnel, disintegrated and frozen at 20C. under nitrogen for 1 hour and then thawed at room temperature for l hour. The freezethaw cycle was repeated 3 times. To the alkali derivative was then added I20 ml. of dimethylsulfoxide (DMSO) and the slurry added immediately to a stirred autoclave. The autoclave was purged several times with nitrogen and 53.2 ml. of ethylene oxide was added (16 equivalents/equivalent of FAQ). The mixture was held at 50C. for 18 hours. The solution was then carefully neutralized with glacial acetic acid, dialyzed and then lyophilized.

The hydroxyethyl derivative can be further purified by precipitating the polymer from aqueous solution with acetone. A freshly precipitated sample of poly[N- acetyl-6-0-(2'-hydroxyethyl)-D-glucosamine] readily dissolved in water. 5% aqueous sodium hydroxide, and 3% acetic acid and is precipitated from these solutions by acetone. Samples analyzed for C, H and N showed the composition to be one in which 1.5 hydroxyethyl groups had been substituted per glucosamine residue.

EXAMPLE X Poly[N-Acetyl-6-0-( Ethyl )-D-Glucosamine] The procedure of Example IX was followed except 75 ml. of ethylchloride was added instead of ethylene oxide and the reaction held at 50C. for hours. A water soluble derivative is obtained.

To obtain an organic soluble derivative, the ethylchloride was mixed with benzene (75% of the amount of ethylchloride). The reaction time was 10 hours and the temperature was controlled as follows: 1 hour heating up to 60C.. 1 hour heating up to 80C., 1 hour heating up to lC. and 7 hours at 130C. An organic solvent soluble product was obtained. The following solvents are useful for solubilization (5% solution) of this polymer at room temperature: 0-xylene. benzene,

toluene. methylethyl ketone. 1.4 mixture of alcohol and benzene. chlorofomi and alcohols.

In the following example using piloearpine free base, the drug is bound ionically to the polymer. The attractive features of such a system are l slower drug delivery and (2) capability of delivering piloearpine as a free base which. as such. has a higher potency. Up to now, it was not possible to deliver piloearpine as the free base since it is unstable in this form and as a result is 0 usually delivered as the hydrochloride or nitrate salt.

EXAMPLE Xl Pilocarpine/Poly[ N'Acetyl-o-(HCarboxymethyl )-D Glucosamine] Inserts A 5% solution of poly[N-acetyl--fl-(carboxymethyl )-D-glucosamine] was prepared in deionized water. The solution was acidified with acetic acid and the polymer precipitated by slowly adding this solution to acetone. The polymer was dried in vacuo at 40C. overnight. Films were prepared from 5% aqueous solutions containing the following relative weights:

PolylN-Acetyl-6-0(Carhoxy- Drug Dose per The films were cut into strips approximately 1 mm X [0 mm weighing 1.5 mg each. In this manner, the drug dosages are delivered from each respective strip. when inserted in the eye.

Effective medication for a treatment day is obtained by placing an insert 1 mm by l0 mm in the human eye.

I claimi l. A method of dispensing an eye drug over a pro longed period of time comprising inserting in the conjunctival sac of the eye a bioerodible enzymatically cleavable occular insert which is shaped to conform to the curvature of the eye and is adapted for insertion and retention in the conjunctival sac of the eye of an eye drug intimately dispersed in an uncoated matrix directly contacting the conjunctival sac of the eye of an enzymatically degradable form of poly( N-acetyl-D- glucosamine) selected from the group consisting of poly[ N-acetyl-6-O-(carboxymethyl )-D-glucosamine poly[ N-acetyl-6-0-( 2'-hydroxyethyl )-D-glucosamine, and poly[ N-acetyl-6-0-( ethyl )-D-glucosamine whereby the said form of poly(N-acetyl-D-glucosamine) is slowly enzymatically degraded by lysozyme in the tears over a period of time, and said eye drug is slowly thereby released into tears, and contacts the eyeball.

2. The method of claim I in which the eye drug is pilocarpine free base or a salt thereof.

3. An enzymatically degradable bioerodible eye drug delivery occular insert device which is shaped to conform to the eye and is adapted for insertion and retention in the conjunctival sac of the eye for administering an eye drug to the eye of a living mammal comprising: an uncoated matrix adapted to directly contact the conjunctival sac of the eye consisting essentially of an enzymatically degradable form of poly(N-aeetyl-D- glucosamine) selected from the group consisting of poly[ N-acetyl6-O-( carboxymethyl )'D-glucosamine poly[ N-acetyl-6-0-( 2 '-hydroxyethyl )-D-glucosamine 1.

and poly[ N-acetyl-6-0-( ethyl )-D-glucosamine], and

intimately dispersed an at least slightly water soluble eye drug.

4. The occular insert of claim 3 in which the eye drug is pilocarpine free base or a salt thereof.

5. A method for dispensing a free base form of an eye drug over a prolonged period of time comprising inserting in the conjunctiva] sac of the eye a bioerodible enzymatically cleavable oecular insert which is shaped to conform to the curvatuve of the eye and is adapted for insertion and retention in the conjunctival sac of the eye of the free base form of an eye drug intimately dispersed in and ionically bound to an enzymatically degradable form of poly[N-acetyl-6-()-(carhoxymethyl)- D-glucosamine], whereby the said poly[N-acetyl-6-()- carboxymethyl)-D-glucosamine] is slowly enzymatibase form of an at least slightly water soluble eye drug. 

1. A METHOD OF DISPENSING AN EYE DRUG OVER A PROLONGED PERIOD OF TINE COMPRISING INSERTING THE CONJUNCTIVAL SAC OF THE EYE A BIOERODIBLE ENZYMATICALLY CLEAVABLE OCCULAR INSERT WHICH IS SHAPED TO CONFORM TO THE CURATURE OF THE EYE AND IS ADAPTED FOR INSERTION AND RETENTION IN THE CONJUNCTIVAL SAC OF THE EYE OF AN EYE DRUG INITIALLY DISPERSED IN AN UNCOATED MATRIX DIRECTLY CONTACTING THE CONJUNCTIVAL SAC OF THE EYE OF AN ENZMATICALLY DEGRADABLE FROM OF POLY(N-ACETYL-D-GLUCOSAMINE) SELECTED FROM THE GROUP CONSISTING OF POLY(N-ACETYL-60-(CARBOXYMETHYL)-D-GLUCOSAMINE, POLY(N-ACETYL-6-0-(2''HYDROXYETHYL)-D-GLUCOSAMINE, AND POLY(N-ACETYL-6-0-(ETHYL)D-GLUCOSAMINE), WHEREBY THE SAID FORM OF POLY(N-ACETYL-DGLUCOSAMINE) IS SLOWLY ENZYMATICALLY DEGRADED BY LYSOZYME IN THE TEARS OVER A PERIOD OF TIME, AND SAID EYE DRUG IS SLOWLY THEREBY RELEASED INTO TEARS, AND CONTACTS THE EYEBALL.
 2. The method of claim 1 in which the eye drug is pilocarpine free base or a salt thereof.
 3. An enzymatically degradable bioerodible eye drug delivery occular insert device which is shaped to conform to the eye and is adapted for insertion and retention in the conjunctival sac of the eye for administering an eye drug to the eye of a living mammal comprising: an uncoated matrix adapted to directly contact the conjunctival sac of the eye consisting essentially of an enzymatically degradable form of poly(N-acetyl-D-glucosamine) selected from the group consisting of poly(N-acetyl-6-0-(carboxymethyl)-D-glucosamine), poly(N-acetyl-6-0-(2''-hydroxyethyl)-D-glucosamine), and poly(N-acetyl-6-0-(ethyl)-D-glucosamine), and intimately dispersed an at least slightly water soluble eye drug.
 4. The occular insert of claim 3 in which the eye drug is pilocarpine free base or a salt thereof.
 5. A method for dispensing a free base form of an eye drug over a prolonged period of time comprising inserting in the conjunctival sac of the eye a bioerodible enzymatically cleavable occular insert which is shaped to conform to the curvatuve of the eye and is adapted for insertion and retention in the conjunctival sac of the eye of the free base form of an eye drug intimately dispersed in and ionically bound to an enzymatically degradable form of poly(N-acetyl-6-0-(carboxymethyl)-D-glucosamine), whereby the said poly(N-acetyl-6-0-carboxymethyl)-D-glucosamine) is slowly enzymatically degraded over a period of time, and said free base form of said eye drug is slowly thereby released into tears.
 6. An enzymatically degradable bioerodible eye drug delivery occular insert device which is shaped to conform to the eye and is adapted for insertion and retention in the conjunctival sac of the eye for administering the free base form of an eye drug to the eye of a living mammal comprising: a matrix consisting essentially of an enzymatically degradable form of poly(N-acetyl-6-0-(carboxymethyl)-D-glucosamine), and intimately dispersed therein and ionically bound thereto, the free base form of an at least slightly water soluble eye drug. 